Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, and the mortality rate from COPD has been increasing over the past two decades. Cigarette smoking is the most important risk factor, but the development of airflow obstruction among smokers is variable. Family studies have suggested a genetic contribution to the development of COPD, but severe alpha 1-antitrypsin deficiency has been the only proven genetic risk factor to date. Previous studies have demonstrated evidence for linkage of COPD to a region on chromosome 19q. We hypothesize that one or more genes that are located on chromosome 19q influence susceptibility to COPD, especially in cigarette smokers, and that these genes can be identified using a high-resolution single nucleotide polymorphism (SNP) mapping strategy. To test this hypothesis, we propose to genotype approximately 1500 SNPs across the linked region in two case control populations. In separate genetic association analyses, cases from the Boston Early-Onset COPD Study will be compared to controls from the Nurses Health Study, and cases from the National Emphysema Treatment Trial will be compared to controls from the Normative Aging Study. Positive associations will be validated in the extended pedigrees from the Boston Early-Onset COPD Study. The use of high-density SNP mapping with association analysis in two case-control samples and validation in a family-based study design should permit the identification of a COPD-susceptibility locus on chromosome 19q, which could result in better understanding of COPD pathogenesis and could highlight pathways and targets for new COPD therapies. The proposed project will train the principal investigator to become an independent investigator in the field of genetic epidemiology of airways disease, through a series of courses, seminars, and supervised research in the areas of genetic epidemiology, molecular genetics, and bioinformatics.